Approximately 1 million people in the United States are at risk for development of iron overload, attributable primarily to the genetic disorder known as hemochromatosis (HH). Once considered a rare disease, HH is now recognized as one of the most common autosomal recessive disorders, occurring in approximately 5 persons per 1,000 in populations of northern European descent. Most patients with hemochromatosis are homozygous for the C282Y mutation in the HFE gene. This inborn error of iron metabolism is characterized by excessive dietary iron absorption and progressive accumulation of iron in the body, typically reaching toxic levels by mid life. The goal of this seeding grant proposal is to plan a collaborative study that will answer the question, "What role do genetic modifiers play in determining iron accumulation in persons homozygous for the HFE C282Y genotype?" A team of investigators will assemble existing data from participants identified through screening studies or clinical practice. Planning for a full-project R24 collaborative study will include secure, web-enabled data capture at study sites, enabling conduct of research projects on the following topics: (1) The prevalence of non-expressors with hemochromatosis;(2) The mechanism underlying low iron re-accumulation after phlebotomy treatment;and (3) The spectrum of disease expression and clinical manifestations of iron overload. With completion of the proposed planning project, the group is expected to be well-positioned to prepare and submit an application for a full-project R24 grant through the NIDDK collaborative Interdisciplinary Research Program in Diabetes, Endocrinology and Metabolic Diseases solicitation (PAR-08-182). The full-project research will provide insight into possible genetic contributions to susceptibility or resistance to iron overload, help to understand the significant variation in iron loading in different individuals with this disorder and the relationship to clinical manifestations, and ultimately lead to development of innovative prevention and treatment strategies tailored to the individual. PUBLIC HEALTH RELEVANCE: The proposed planning project is expected to lead to a full-project research study that will provide insight into possible genetic contributions to susceptibility or resistance to iron overload. Results will help to understand the significant variation in iron loading in different individuals with this disorder and the relationship to clinical manifestations, and ultimately lead to development of innovative prevention and treatment strategies tailored to the individual.